Stabilized cefuroxime axetil

ABSTRACT

Solid pharmaceutical compositions comprising cefuroxime axetil as active ingredient and a zinc salt as stabilizer.

BACKGROUND

[0001] Cefuroxime axetil is an antibiotic effective against a widespectrum of microorganisms when administered orally.

[0002] Solid compositions for oral administration comprising cefuroximeaxetil are presently available commercially in the form of tablets, andas powders for oral suspension.

[0003] There are substantial difficulties in the production ofsatisfactory solid compositions comprising cefuroxime axetil.

[0004] One problem is that it is difficult to make compositions for oraladministration which provide high bioavailability; that is to say, thatare well absorbed from the gastrointestinal tract into systemiccirculation. In particular, if the cefuroxime axetil is in crystallineform, it exhibits poor water solubility and hence poor absorption.

[0005] U.S. Pat. No. 4,820,833 discloses that absorption can be improvedby using cefuroxime axetil in pure amorphous form instead of crystallineform.

[0006] U.S. Pat. No. 4,897,270 further discloses that absorption fromfilm coated tablets can be improved by formulating the tablets suchthat, when a tablet is ingested, the film coating ruptures rapidly inthe gastrointestinal fluid, and the core then disintegrates immediately.

[0007] Canadian patent no. 2209868 discloses that, instead of usingcefuroxime axetil in pure amorphous form, excellent dissolution andabsorption can also be achieved by using cefuroxime axetil in the formof a co-precipitate of cefuroxime axetil and a water-soluble excipient.

[0008] A second problem in formulating satisfactory solid compositionscomprising cefuroxime axetil is that cefuroxime axetil is relativelyunstable in the presence of many common excipients (i.e. inactiveingredients) used to make solid pharmaceutical compositions.

[0009] The object of the present invention is to provide a means ofstabilizing cefuroxime axetil, so as to reduce the rate of degradationof cefuroxime axetil in solid pharmaceutical compositions.

DESCRIPTION OF THE INVENTION

[0010] It has been surprisingly found that cefuroxime axetil can bestabilized by admixture with a zinc salt, preferably zinc chloride.

[0011] Compositions of the present invention will thus be solidpharmaceutical compositions comprising cefuroxime axetil as activeingredient and a zinc salt as stabilizer.

[0012] The amount of zinc salt in the composition will preferably befrom about 0.1 to about 4 parts per 100 parts cefuroxime axetil byweight; more preferably from about 0.2 to about 2 parts per hundredparts cefuroxime axetil by weight; and most preferably about one partper hundred parts cefuroxime axetil by weight.

[0013] In order to enable maximum bioavailability, the cefuroxime axetilin the composition will preferably be in pure amorphous form or in theform of a co-precipitate with a water-soluble diluent.

[0014] The zinc salt may be added to the composition at any point in theprocess of production of the composition.

[0015] However, when the cefuroxime axetil is used in pure amorphousform or in the form of a co-precipitate, the zinc salt will preferablybe added, in the process of making the pure amorphous cefuroxime axetilor the co-precipitate, in order to get a more intimate mixture of thezinc salt with the cefuroxime axetil.

[0016] In the case of pure amorphous cefuroxime axetil, the process ofmanufacture will preferably be to dissolve the zinc salt along with thecefuroxime axetil in suitable solvent and then evaporate the solvent,preferably by spray-drying, in order to produce amorphous materialcomprising cefuroxime axetil and a small amount of zinc salt intimatelymixed therein.

[0017] Similarly, in the case of a co-precipitate, the process willpreferably be to dissolve the cefuroxime axetil, water-soluble diluent,and zinc salt together in suitable solvent and evaporate the solvent,again preferably by spray-drying to produce an amorphous co-precipitatecomprising the cefuroxime axetil, water-soluble diluent, and zinc salt.

[0018] The amorphous material comprising cefuroxime axetil and zincsalt, or cefuroxime axetil, water-soluble diluent, and zinc salt, willthen be further processed into the final solid composition which, asaforesaid, may be a tablet, or a powder or granules for oral suspension;that is to say, powder or granules to which water is to be added toprovide a suspension for pediatric use.

[0019] The invention will be further illustrated by the followingexamples, which are intended to be illustrative but not limiting of thescope of the invention.

[0020] Solutions were made by dissolving cefuroxime axetil, sorbitol andzinc chloride in acetone and water in the proportions shown. ExampleExample Example Example #1 #2 #3 #4 Cefuroxime axetil 90. 90. 90. 90.Sorbitol 10. 9.6 9.0 8.0 zinc chloride 0 0.4 1.0 2.0 Acetone 400 400 400400 Water 100 100 100 100 600 600 600 600

[0021] Each of the solutions of examples 1 to 4 was then spray-dried toproduce an amorphous co-precipitate comprising 90% cefuroxime axetil byweight.

[0022] On a dried basis, the percentage of zinc chloride by weight wasnil in example 1, 0.4% in example 2, 1% in example 3, and 2% in example4.

[0023] In each case, the spray-dried co-precipitate was furtherprocessed by mixing the co-precipitate with other ingredients in thefollowing proportions. Co-precipitate 694. Crospovidone 358. Zincstearate 8. 1060.

[0024] In each case, the mixture was then compressed into tablets ofweight 1060 mg per tablet. Each tablet thus contained 694 mg ofco-precipitate, which in turn comprised 90%×694 mg or 624.2 mg ofcefuroxime axetil, which is equivalent to about 500 mg of cefuroxime.The crospovidone is a disintegrant, and the zinc stearate is a lubricantto prevent sticking to the tooling in the tabletting process.

[0025] The tablets of each of these examples were then subjected to anaccelerated stability trial, in which samples were stored at 60° C. for7 days. The samples were then tested to determine the amount by whichrelated impurities (i.e. degradation products) increased during the 7days at 60° C. The results were as follows: Example Example ExampleExample #1 #2 #3 #4 % zinc chloride in   0%  0.4%   1%   2%co-precipitate increase in RC1 0.29% 0.12% 0.06% 0.05% increase in other0.09% 0.11% 0.11% 0.17% impurities increase in total 0.38% 0.23% 0.17%0.21% impurities

[0026] It can be seen that the increase in RC1 upon storage at 60° C.for 7 days was 0.29% for the tablets of example 1, which contained nozinc chloride. The increase was less for examples 2, 3, and 4, but notsignificantly less for example 4 than for example 3.

[0027] On the other hand, the increase in other impurities was morerapid as the level of zinc chloride is increased. The increase in totalimpurities was the least for example 3, which had 1% zinc chloride inthe co-precipitate.

[0028] Since the co-precipitate of example 3 comprised 90% cefuroximeaxetil, and 1% zinc chloride, the most preferred amount of zinc chlorideis concluded to be about 1 part per 100 parts cefuroxime axetil byweight.

What is claimed is:
 1. A solid pharmaceutical composition comprisingcefuroxime axetil and a zinc salt.
 2. A composition of claim 1, whereinthe zinc salt is zinc chloride.
 3. A composition of claim 1 or 2,wherein the amount of zinc salt is from about 0.1 part to about 4 partsper 100 parts cefuroxime axetil by weight.
 4. A composition of claim 1or 2, wherein the amount of zinc salt is from about 0.2 to about 2 partsper 100 parts cefuroxime axetil by weight.
 5. A composition of claim 1or 2, wherein the amount of zinc salt is about 1 part per 100 partscefuroxime axetil by weight.
 6. A composition of any of claims 1 to 5,in the form of a tablet.
 7. A composition of any of claims 1 to 5, inthe form of powder or granules for oral suspension.
 8. A process ofstabilization of cefuroxime axetil comprising the step of addition of azinc salt to the cefuroxime axetil.
 9. A process of claim 8, wherein thecefuroxime axetil and zinc salt are both dissolved in solvent and thesolvent is evaporated.
 10. A process of claim 8 or 9, wherein the zincsalt is zinc chloride.